AT397655B - Process for the preparation of novel substituted ethanediimidamides - Google Patents

Description

5

AT 397 655 B

The present invention relates to a process for the preparation of a compound of the general formula

II 10 wherein R1 is a hydrogen atom, (nlodrig) alkyi, or

IS 30 means, where p is K3r 1 or 2 and R * and H9 each independently represent a hydrogen atom, (lower) alkyl, {lower) alkoxy or hatogen atom, m is an integer from 0 to 2 inclusive, 23 n is an integer from 2 to 5 inclusive; Z represents an oxygen or sulfur atom or methylene, and Aför

where 45 R5 is a hydrogen atom or (lower) alky! q is an integer from 1 to 4 inclusive and RE and R7 each independently represent {lower) alkyl, or R * and R7, together with the nitrogen atom to which they are attached, represent a pyrrolidino or piperidino radical , or a salt, hydrates or solvates thereof.

The process according to the invention is characterized in that, preferably in an inert solvent and at room temperature, a compound of the general form! 2 55

III 5, 1 AT 397 655 B

A-tCH2) mifCB2) nSH

WATCH “10 where R1. A and Z and m and n have the meanings given above, reacted with a strong inorganic acid, preferably hydrochloric acid.

The compounds of the general formula II prepared according to the invention form 3- (amino or substituted amino) -4- (substituted amino) -1,2,5-thiadiazoles of the general formula 20 with sulfur mono- »5 or dichloride with ring closure

1 wherein A, m, Z, n and R1 have the meanings given above.

These substituted thiazofes of Formula I and their non-toxic, pharmaceutically acceptable salts, hydrates and derivatives are potent histamine hfe receptor antagonists which inhibit gastric acid secretion 30 and are useful in the treatment of peptic ulcer and other pathological hypersecretions. All possible tautomers, diastereoisomers and optically active isomers of the compounds of the formula I and mixtures thereof also have an effect. The term used (low) * alkyl stands for a straight-chain or branched alkyl group which contains 1 to 6 carbon atoms. The term " (low) alkoxy " represents a straight-chain or branched alkoxy group which comprises 1 to 4 ae carbon atoms

The term " non-toxic pharmaceutically acceptable salts " means acid addition salts which are mixed with acids, e.g. Hydrogen chloride, hydrobromic acid, nitric acid, sulfuric acid, acetic acid, propionic acid, fumaric acid-methanesulfonic acid, maleic acid, tartaric acid, citric acid, laevuic acid. Benzoic acid, succinic acid and the like are formed. 40 In the compounds of formula 1, R1 preferably represents a hydrogen atom or (lower) alkyl, more preferably represents a hydrogen breath or methyl and most preferably TGr represents a hydrogen atom. The substituent A is preferably the substituted phenyl group, the substituted furyl group or the substituted thienyl group as shown above, and is most preferably the substituted phenyl group. The substituent Z is preferably a sulfur or oxygen atom and, if A is the substituted phenyl radical, Z is preferably 4S an oxygen atom. M is preferably 0 or 1 and n is 2 or 3, and when A is the substituted phenyl radical, m is 0 and n is 3. R * is preferably a hydrogen atom or methyl and most preferably a hydrogen atom, preferably q is 1 R6 and R7 are preferably (lower) -alkyl, or together with the SScksfofftrtom to which they are attached, pyrraiidino or piperidino.

The published GB application 2,067,987 describes 3,4-disubstituted-f, 2,5-thiadiazoM -oxides and so 1,1 -dioxide of the formula

SS 3 5 ΑΤ397Θ55Β

A - ^) aZICH2) aKH

ία and process for their preparation, wherein the residues A, m, Z, n and R1 are similar to the residues disclosed and claimed above. However, the compounds described there are 1-oxides or 1,1-dioxides (p stands for 1 or 2), and the compounds of the form? I cannot be prepared by the methods used to prepare the prior art compounds. 7s The published European Patent Application No. 40 696 describes, inter alia, 3,4-disubstituted-1,2,5-thiadiazoI-oxides and 1,1-dtaxides of the general formula:

St — ®— (CH2) n-X- (CSj)

30 and process for their preparation, the radicals R, A, η, X m, R1 and R2 being similar to the corresponding substituents of the compounds described and claimed here. However, the compounds described herein are also 1-oxides or 1,1-dioxides (p = 1 or 2) and the compounds of Formula I cannot be obtained by any of the methods for preparing the compounds of the prior art. 35 In the two publications mentioned above, each of the processes described for the preparation of the compounds according to the prior art comprises the use (as starting material or intermediate) of a 1,2,5-thiadiazoM-oxide or -1,1-dioxide. which has either amino groups or suitable leaving groups at the 3 or ^ positions. The desired substituents at the 3 and 4 positions are then obtained by substitution on the amino groups or by replacing the "leaving-40" groups.

The compounds of formula I can be prepared by reacting a compound of formula II with sulfur monochloride (82 (¾) or. Sulfur dichloride (SCfe) as listed below 50 4 55

AT 397 655 B zz A " < ch2 > »* (CH2 - ^ w * 1 S2C12 or 2 be Α- < <: Η2 > * 2 f

Z wherein A, m, Z, n and R1 have the meanings given above. At least 1 Mof SsCb or SCb should be used per Mbl compound fl: preferably an excess of $ 2% or SCb is used. e.g. about 2 to 3 moles of 82Gb or SCb per mole of Compound II. It has been found that SCb often results in a crude product and a lower amount of purified product. We normally prefer 82 (%.

The reaction temperature is not critical; the reaction is preferably carried out at a temperature of from 0 ° C. to about 50 ° C. It is best to listen to the reaction at ambient temperature. The reaction time is not critical and depends on the temperature. A reaction time of about 30 minutes to about 6 hours is normally used. At ambient temperature, reaction times are from about 1 1/2 to 4 hours normally preferred The reaction can be carried out in an inert organic solvent, preferably a mixture of an inert organic solvent and dimethylformamide, most preferably the reaction is carried out in dimethylformamide

According to a preferred embodiment, the compounds of formula 1 have the following structure: 1 A-tCK2) Ä2 CCK2) aNH% s_JHJR1 Ίπί

Ns- 'wherein R1 is a hydrogen atom or (lower alkyl), m is zero or 1 and n is 2 or 3, Z is an oxygen atom and A is 5

AT 387 656 B

in which ff represents a hydrogen atom or methyl, and ff and ff each independently represent methyl or ethyl ·, or together with the nitrogen atom to which they are attached form a pyrrolidine or piperidino ring. or a non-toxic, pharmaceutically acceptable set, hydrate or sotvate thereof.

According to a more preferred embodiment, the compounds of the formula I have the structure Ia:

la h2ch2ch2nh / rC ’where R * represents a hydrogen atom or methyl, and ff and R7 each represent methyl, or together with the substance atom. to which they are bound mean pyrraidino or pipendino ring; or a non-toxic, pharmaceutically acceptable salt, hydrate or sotvate thereof.

In another more preferred embodiment, the compounds of Formet I have the structure

wherein H1 and ff each independently represent a hydrogen atom or methyl, and R5 and R7 independently represent methyl or ethyl; or a non-toxic, pharmaceutically acceptable salt, hydrate or soivate thereof. 6

AT 397 655 B

According to a further preferred embodiment, the compounds of the formula I have the structure Ic:

Xc wherein R1 and R5 each independently represent a hydrogen atom or methyl and R6 and R7 each independently represent methyl or ethyl; or a non-toxic, pharmaceutically acceptable salt, hydrate or soivate thereof.

The currently most preferred compounds of formula I are: 1) 3-amino-4- [3- (3-piperidinomethytphenaxy) propylamino] -l, 2,5-thiadiazof, 2) 3-amino-4- 2 - [{ 5-dimQthyIaminomeBtyi-2-furyi) methylthio @ thylamino -1,2,5-thiadiazole; 3} 3-amino-4- 2 - [(5-dimethyaminomethyi-4-methyF2-thlenyl) methylthio] ethylamino -1,2,5-thiacfiazoi; 4) 3-Amino4- [3 ^ 3-pyrroidlnomathyIphenoxy) propylamino] -1, 2,5-fhiadiazoi, 5) 3-Methyiaminc-4- [3- (3-piperidinomethylphenoxy) propylamino3-1,2,5 * thiadiazole. 8) 3-Benzylamino-4- [3- < 3-piperidinomothylphenoxy) propylamtno} -1, 2,5-thiadiazoi, 7) 3-Amino-4- {2-E (S-dimethyiamirtome »iyl-3-thienyl ) methylthio] ethylamino} -1,2,5-thiadiazot, 8) 3-Am! no-4- {2-i (5-piperidinome-ethyl-3-thienyl) methyithio] sthytamino} -1, 2,5-thiaciiazole, and their non-toxic, pharmaceutically acceptable salts, hydrates and solvates.

The process according to the invention for the preparation of the compounds of the general formula II is illustrated by the following reaction scheme:

xzx% HCl

V xx A- (CH2 > äZ (CH2) n «Hv yKHHr

The reaction can be carried out in an inert solvent and is preferably carried out in methanol. The reaction temperature is not critical; the reaction is most preferably carried out at room temperature. The compounds of the formula Hl are known or can easily be obtained using process 7

AT 397 655 B1 are stiffened as described in British Patent 2,067,987.

According to a preferred embodiment, the products of the formula II have the structure II:

BN NX

IX where R1 is a hydrogen atom or (lower) alkyl, m is zero or 1, n is 2 or 3. Z represents an oxygen or sulfur atom and

For

where R5 represents a hydrogen atom or methyl, and Fl6 and R7 each independently represent methyl or ethyl, or together with the nitrogen to which they are attached represent a pyrrolidino or piperidino ring; or a non-toxic, pharmaceutically acceptable salt, hydrate or soivate thereof.

According to another preferred embodiment, the products of the formula II have the structure ila:

ila in which R1 represents a hydrogen atom or methyl, and RP and R7 each represent methyl, or together with the nitrogen atom to which they are attached represent a pyrrolidino or piperidino ring; or a salt, hydrate or solvate thereof,

According to a preferred embodiment, the products of the formula II have the structure IIb: 6

AT 397 655 B

IXb wherein R1 and FP each independently represent a hydrogen atom or methyl, and R6 and R7 each independently represent methyl or ethyl; or a salt, hydrate or sofvate thereof. According to another preferred embodiment, the products of the formula II have the structure Hc:

ZIe äs wherein R ’and R5 each independently represent a hydrogen atom or methyl, and FR and R7 are each independently methyl or ethyl; or a salt. Hydrate or sofvat thereof.

The most preferred products of formula II are: 1) N- [3- (3-piperidinomethylphenoxy) propyl] ether diimidamide. 2) N- {2 - [(5-DimetoytamincvnethyP2-ftjryl) methy (thiojathyl} äthandifmfdamid, see 3) N- {2 - [(5-Dimethyiaminomethyl-4 * methyl «2-thienyl) methylthio] äthyl} äthandilmidamid, 4 ) N - [- 3- {3-Pyrroildinomethylphenaxy) propyl] äthandiimidamid, 5) N- {2 - [{5-Dimethyiaminonfiettiyt “3-thienyl) methyitiiio] äthyl} äthandiimidamid. or a salt, hydrate or solvate thereof.

For therapeutic use, the pharmacologically active compounds of formula I 35 are normally administered as a pharmaceutical agent which contains the active ingredient in its basic form or in the form of a non-toxic, pharmaceutically acceptable acid addition salt, together with a pharmaceutically acceptable carrier

The pharmaceutical agents can be administered orally, parenterally or rectally as suppository. A wide variety of pharmaceutical forms can be used. Thus, if a solid carrier 40 is used, the preparation can be made into tablets, put in powder or pellet form in a hard gelatin capsule, or in the form of a lozenge or lozenge. If a liquid carrier is used, the preparation can be used as a syrup. Emulsion, soft gel cap, sterile solution for injections or as an aqueous or non-aqueous liquid suspension. The pharmaceutical agents are manufactured according to conventional methods suitable for the desired preparation. 45 The dosage of the compounds depends not only on factors such as the weight of the patient, but also on the degree of gastric acid inhibition desired and the effectiveness of the compound used. The doctor decides which dose to use (and the number of administrations per day) and can be varied depending on the specific circumstances and the patient.

In the preferred compounds, each oral unit dose contains the active ingredient in an amount of from about 2 mg to about 300 mg, and most preferably from about 4 mg to about 100 mg. The active ingredient is preferably administered in equal doses 1 to 4 times daily

Histamine Fb reseptor antagonists indicated that they are effective inhibitors of gastric secretion in animals and humans, Brimblecombe et al., J. Int Med. Res., 3, 86 (1975). Clinical evaluations of the histamine hfe receptor antagonist cimethidine showed that it is an effective therapeutic for the treatment of peptic ulcer, Gray et al, Lancet, 1, 8001, (1977). Some of the preferred compounds were compared to cimethidine in various tests and found to be stronger than cimethidine, both as a histamine 1-fe receptor antagonist tested on the isolated right guinea pig atrium and as an inhibitor of gastric acid secretion Rats and dogs. 9 ΑΤ397Θ55Β

Determination of gastric anti-secretion effects in rats with gastric fistula

Male Long Evans rats weighing approximately 240 to 260 g were used in the implantation of the cannula. The type of implantation of the stainless steel cannula in the foreleg of the foreskin is essentially carried out as described by Pare et al. [Laboratory Animal Science, 27. 244 (1977JJ. The Rstei constituents are determined and the operation is carried out exactly as described in the above-mentioned parts of the literature.

After the operation, the animals are kept individually in cages with a solid bottom with sawdust and are given food and water ad libitum during the entire recovery period. The animals are not used for test purposes at least 70 days after the surgery.

The animals are fasted before the test, but water is given ad libitum 20 hours before the test. Immediately before collecting the secretion, open the cannula and gently wash the stomach with 30 - 40 ml of warm saline or distilled water to remove all residues. The catheter is then screwed into the cannula at the place where the locking screw used to be and the rat 75 is placed in a light, rectangular plastic cage that is 40 cm long, 15 cm wide and 13 cm high. The bottom of the cage has a slot about 1.5 cm long and 25 cm long, which runs through the middle and through which the catheter exits. In this way, the rat is not restricted and can move freely in the cage during the collection times, otherwise the experiment is carried out as described by Ridley et al. described [Research Comm. Chem. Pharm., 17.365, {1877) 3. 20 The gastric secretions collected during the first hour after washing the stomach are discarded as they may be dirty. For oral evaluation, the catheter is then removed from the cannula and replaced by the locking screw. 2 ml / kg of water are given orally by gastric intubation and the rate is left in the cage for 45 minutes.

Then the screw plug is loosened and replaced with a catheter that carries a small plastic bottle and collects the gastric secretions. A 2-hour sample is collected (this represents the control secretion), the catheter is removed and replaced with the screw plug. Then the test compound is given orally in a volume of 2 ml / kg by gastric intubation. 45 minutes later, the screw plug is opened again, replaced by the catheter to which a small plastic vial is attached, and another 2-hour sample is collected. The secretions in the second sample are compared to those of the control sample to determine the effect of the compound tested to determine.

If the test compounds are evaluated parenterally, the animal is i.p. or s.c. the test compound carrier is injected in an amount of 2 ml / kg. Immediately beforehand, the initially obtained solution collected over 60 minutes is discarded. A 2-hour sample is collected (control roll secretion) and the animals are then either injected i.p. or s.c. the test compound in an amount of 2 ml / kg. A further 35 2-hour sample is collected, these secretions are compared to those of the control to determine the effect of the drug.

The samples are centrifuged and placed in a graduated centrifuge tube for volume determination. Titrable acid is measured by titrating a 1 ml sample to pH 7.0 with 0.02N NaOH using an autoburette and an electronic pH meter (radiometer). The titratable 40 acid output is calculated in micro equivalents by multiplying the volume in milliliters by the concentration of miliequivalents per liter

The results are expressed as percent inhibition based on the contral readings. Dose-response curves are set up and EDsq values are calculated by regression analysis. At least 3 rats are used for each dose and at least 3 doses are used to determine the dose-response curve so ss 10 5

AT 397 655 B

Table 1

TO

Gastric antisecretion activity, tested on rat with gastric fluff compound EDso sc umote / kg potency ratio (cimethidine = 1.0) cimefhidine 3.48 (1.66-5.75} + 1.0 Example 1B 0.094 (0.043-0.20) 37 Example 28 0.77 (0.45-1.4) 4.5 Example 3B -0.5 -7 Example 46 0.18 (0.10-0.36) 20 * 95% confidence limit

Histamine-tfe receptor antagonism, tested on isolated guinea pig preparations

Histamine causes increases in the contractions of concentrate guinea pigs isolated, spontaneously beating right, depending on the concentrate. Blade et a! “Nature, 236, 386 (1972) described the receptors that were involved in this action of histamine as histamirHHz receptors when they reported the properties of burinamide, your antagonist of these receptors. Later investigations by Hughes and Coret, Proc. Soc. Exp. BioJ. Med-, 148-127 (1975) and Verma and McNeill, J. Pharmscof. Exp. Ther., 200, 352 (1977), Schloß von Black and co-workers confirmed that the 25 positive chronotropic effect of histamine on damaged right guinea pig vestibules is mediated by histamine Hi receptors. Black et ai., Agents and Actions, 3, 133 (1973) and Brimblecombe et al., Fed. proc., 35, 1931 (1976) used isolated right atria from guinea pigs to compare the effects of histamine Hj receptor antagonists. The present comparative studies were carried out using a modification of the von Reinhardt et af .. Agents and Actions. 4, 217 30 (1974). Male Hartly Stemm guinea pigs (350-450 g) were killed by a blow to the head. The heart was removed and placed in a petri dish in which oxygenated (95% 02, 5% CQ2) modified cancer solution was praying {g / Uter: NaCt 6.6; KCl 0.35, MgS0 ". ≫ 7H20 0.295, KH2PO" 0.162, CaCIz 0.238, NaHCOs 2.1 and Dextrose 2.09). The spontaneously beating right atrium was freed of 35 other tissues and a silk thread (4-0) was attached to each end. The atrium was suspended in a 20 ml muscle chamber containing oxygenated modified crab solution which was kept at 32 ° C. The atrial contractions were recorded isometrically with a Grass FT 0.03 force transducer and the contraction force and speed were recorded with a Bookman RP Dynograph 40 A permanent tensile force of 1 g was applied to the atrium, in which state the preparation was left for 1 hour stand. A submaximal concentration of histamine dihydrochloride (3.10 ^ M) was then added to the bath and washed out to prepare the tissue. Then the bath histamine was added cumulatively in 1/2 log 10 intervals, so that sad final concentration from 1.10-1 to 3 x 10 "5 Mot was obtained. The hemostemic-induced increase in beats of the heart chamber was allowed to settle before the 49 next concentration was set. Maximum responses were made each time at a dose of 3 x 10 ~ s M. The histamine was washed out several times and the atrium was returned to the control value. Then the test compound was added at appropriate molar concentrations and after a 30 minute incubation the response to the histamine dose was repeated with the higher concentrations adjusted as needed. 50 The dissociation constants (Kg) were calculated from the Schild curves using the method of Aruniakshana, O. and Schild, H.O. [Br. J. Pharmacol, 14, 48, (1959), whereby at least 3 dose units were used as a basis. Parallel shifts in dose-response curves were obtained without reducing the maximum response at the antagonist concentrations used. The results are shown in Table 2. 11

AT 397 955 B

Table 2

Activity on isolated right guinea pig atria Compound N Kb (UMol) Efficacy ratio {cimethidine «1.0) Cimethidine 20 0.41 (0.21-0.64) + 1.0 Example 1B 12 0.003 (0.001 -0.004) 137 Example 4B 11 0.004 {0.001 - 0.010) 102 + 95% confidence limit

The compounds of formula I can also by ring closure of a compound of formula II with N, Ν’-thlobisphthalimld of the formula:

getting produced.

The use of N.N'-thtobisphfhalnmid instead of S2CI2 or SCb for the ring closure gives both higher and purer yields of compounds of formula 1. The crude products of the formula I thus produced are normally pure enough to form crystalline batches directly, without prior chromatographic purification

In this process, the dümidamide of Formet II used as the starting product is reacted with an approximately equivalent amount of N.N'-thiobisphthaHmid in an inorganic inert solvent, such as CHaCh. Preferably, the diimidamide is used in the form of its trihydrochloride content, in which case three molar equivalents of an amine, such as triethylamine, may be added to the reaction mixture to neutralize the trihydrochloride salt. The reaction can be carried out by stirring at room temperature for about t hour to ensure the completion of the reaction. The PMhaiimid that precipitates from the reaction mixture is then extracted with a strong base (e.g. 10-20% aqueous KOH) and the organic solvent is dried, filtered and concentrated to give the crude product of the compound of formula i . The N.N'-thiobisphthalimide used in the present invention is a known compound which can be stiffened as described in Canadian Journal of Chemistry, 44, 2111-2113 (1968) or as described below.

Production of N.N’-Thiobfsphthalimid

5.15 g (0.05 mol) of sulfur dichloride are added dropwise to a cooled solution (0 ° C. > of 14.7 g (0.1 mol) of phthalimide in BO with dimethylformamide (DMF), and the mixture is left to stand within 4 after the addition Heat for 20 hours at 20 ° C., collect the solid and dry, yielding 12.5 g of the titanium compound as DMF-Sotvat, mp 301-315 ° C. Both the IR and the NMR spectra are inconsistent with the structure. 12th

AT 397 655 B

Analysis for CicHsffeOtS'CsKrNO: C H N S calculated found: 57.42 57.50 3.80 3.80 10.57 10.29 8.07% 8.57%

Obs DMF-Soivat can be removed from the substance by recrystallization in chloroform. The mp of the DMF-free product is 320-325 ° C. No DMF could be seen in the NMR spectrum. io

Analysis for CieHgNzQt $: C H N 8 calculated 59.25 2.48 8.64 9.89% found: 59.21 2.21 8.91 10.14%

The following examples show the preparation according to the invention of the new compounds II and their further processing to give the compounds I.

Example 1: Preparation of N- [3- (3-piperidinomethylphenoxy) propyl] äthandiimidamide trihydrochloride. A. N- [3- (3-Plperidlnamethylphenoxy) propyl] äthand! Lmlciatnid -trihydrochtortd

A suspension of 17.1 g (47.0 mmol) of 3-amino-4- [3- (3-piperidtnomethylphenoxy > ss propylamino > 1,2, & thiadiazole-1-oxide [prepared according to the published GB patent application 2 067 9B7} in 450 ml of methanol with 38 ml of concentrated HCl, the solution obtained is stirred for 3 hours at room temperature, the solution is concentrated and the water is removed azeotropically with absolute ethanol to give colorless crystals, which are suspended in 200 ml of absolute ethanol, filtered and dried in vacuo to give 16.6 g (82.6%) of the titanium compound, mp 205 to 220 ° C. (dec.) 30 Crystallization from 50% methanol / ethyl acetate gives an analytical sample with mp 206-216 ° C (dec.).

Analysis for Ci7H £ 7NsO * 3HCI: CHN calculated: 47.84 7.08 16.41% found: 47.56 7.18 16.75% 40 B. 3-Amino-4-E3- (3-Pip6ridiromethylphenoxy) propylaminoH , 2.5- * hiadiazole

A stirred suspension of 2.13 g (5.0 mMoi) of N-f3- (3-piperidinometbylphenoxy) propyi] -äthandiimidamic-trihydrochloride [produced in stage A] in 20 ml of dimethylformamide (DMF) is mixed with 2.02 g ( 15.0 mmol) of sulfur monochloride, stirred for a further 4 hours, carefully poured the resulting mixture into 200 ml of water and made basic with KiCOa. The mixture is then extracted with 3 × 50 ml of methylene chloride, 45 is dried over MgSO * and concentrated to give 2.1 g of a dark gummy product. The product is purified by HPLC chromatography on sitica, CH2C (2 (100): 2 -Propanol (10): NH + OH (0.5) used as the mobile phase. The appropriate fractions yield 0.89 g of the title compound, from which 0.76 g (21.4%) of the title compound as fumaric acid in n-propanol crystalline fumarate must be obtained, mp. 187 * 187.5 ° C. Purity according to HPLC> 99%

Analysis for (Ci7H25Ns0S) 2aCtH * .04: C H N S calculated: 56.27 6.71 17.27 7.90% found: 56.09 6.36 16.96 8.08% 13

AI 397 655 B

A portion of the fumarate is suspended in water, neutralized with KjCOa, extracted with CHaCb and concentrated with CHaCb and the CHaCb phase is concentrated, the free base of the title compound crystallizing, mp 43-47 ° C. Part of the free base is converted into the hydrochloride salt, mp. 138-140 ° C.

Analysis for CirfbsNsOS'HCl: calculated C H N S found: 53.18 53.14 6.83 8.88 18.24 18.49 8.35% 8.74%

Example 2: Preparation of N- {2 - [(5-Dimethylaminomethyl-2-furyl) methyithio] Sthy1V3thandiimidamid-trih-te ydrochlorhydrate A- N-f2 - [(5-Dimethylaminomethyl-2-furyOrnethylthtoläthyl) -äthandiimidamidhydratehydrochloride of 6.59 g ¢ 20.0 mmol) 3-amino-4- {2-E (5-dimethylaminomemyl-2-furyl) methylthio] -§thyiamino > -1, 2,5-thiadiazoM-oxide [prepared according to the published GB patent application 2 067 so 987] in 200 ml of methanol is slowly warmed to achieve a complete solution. Then 13.3 ml of conc. HCi, stirred for a further 2.4 hours at room temperature, concentrated the solution and triturated the residue with 70 ml of absolute ethanol. The crystals are filtered off and dried in vacuo to give 4.3 g (52%) of the titan compound. Mp 186-169 ° C (dec.).

Analysis for C32H21 ffeOS »3HCI · H2O: CHNS calculated: 35.08 6.38 17.05 7.80 found: 34.85 6.24 17.45 7.97 B. 3-Amino-4- (2 - [(5th -Dimethylaminomethyi-2-furyl) methylthioffithylaTnino} -1,2,5-thiadiazole To a stirred suspension of 12.3 g (30.0 mmol) of N- {2 - ((5-Dimefliylammomsfhyl-2-, fuiyl) -methylthio ] äthyl} äthandümidamid-trihydrochloridhydrst [prepared in step A] in 150 ml of DMF are added 38 7.2 ml of sulfur imanochloride (12.1 g, SO mmol), stirred for a further 4 hours at room temperature, removed about half of the DMF under reduced pressure , the remaining black solution is poured into 1 liter of water, made basic with feCO and extracted first with ethyl acetate and then with chloroform. After drying over MgSO 4, the mixture is filtered and concentrated to give 9.0 g of a black, gummy product , which contains the product, which is purified by HPLC chromatography on Sifica, 40 using ethyl acetate (100): 2-propanol (10) -NHiOH (0.5) as the mobile phase The appropriate fractions give 1.24 g of the titan compound as a rubber-like product

Treatment of parts of this product with an equivalent amount of 2N HCi in methanol gives the hydrochloride salt of the titan compound.

Analysis for CiaH ^ ffeSaO-HCt: C H N 8 calculated 41.18 5.76 20.02 18.33% found: (corr. For 1.65% H2O) 40.54 5.70 19.38 18.44%

4S 50

Treatment of the product with an equivalent amount of Cydohexylsuffamtdsäure in acetone gives the CyclohexyteuifematsaJz the Titeiverbblung, mp. 93-95 ° C.

5G 14

AT397 655B

Analysis for Ci 2 Hi a Ns S2 0C6 Hi s NOaS: C H N S calculated 43.88 6.55 17.06 19.53% found: 43m77 6.17 17.21 19.58%.

Example 3; Preparation of N- (2-f (Dimelhyteminom & thyi-4-methyl-2-toienyi) -rnathyltbio] -10 ätyi) äthandiimidamid-frihydrochloride A. N- {2-i (5-Kmetfiylaminomethyl-4-me &); yi -2-thienyQmethyithio3ättiyi > athandiinriidamid-trihycfrochloride A stirred solution of 17.9 g (50.0 mmol) of 3-amino-4 ~ {2 - [(5-dlmeihylaminam0thyl-4 ~ methyl-2-thienyl) methyl! Hia3äthyteinino } " l, 2,5 ^ äiiadiazoM-oxide (prepared according to the general procedure described in 15 of published QB patent application 2,067,987) in 500 ml of methanol with 33 ml of conc. HCl, stirred for a further 3 hours, concentrated the reaction mixture and removed excess water by azeotropic constriction with absolute ethanol, giving an almost colorless crystalline residue. The residue was triturated with 200 ml of absolute ethanol at 0 ° C. filtered and dried to give 18.9 g (80%) of the trisl compound F.P. 208 - 220 ° C (dec.) So recrystallization from 80% methanol / ethyl acetate gives a product with mp. 210-221 ° C (dec.).

Analysis for CiaHaaNsSz ^ HCi: c H N δ calculated 36.92 6.20 16.56 15.17% found: 36.76 6.33 16.97 15.54%. B. 3-Amino-4 {2-t (5-dimethylaminomethy <-4 * m8thyl-2-thienyl) -rnethytfriio] äthytemino} -t, 2,5-thiadiazole 30 To a tube suspension of 8.34 g (15 , 0 mmol) N- {2- £ (5-DimethylaminomethyM-metoyl-2-thienyl) methylthio] äthyi} äthandiimldamld trihydrochtorid [prepared in stage A] 6.1 g (45.0 mmol) are added to 80 ml DMF. Sulfur monochloride, stirred for 4 hours at room temperature, pour the reaction mixture into 800 ml of water, make basic with K2CO3 and extract several times with 100 ml of methylene chloride. The extracts are dried over Mg SO 4, filtered and concentrated to give 3.4 g of a black, gummy product. This is purified by preparative HPLC chromatography on silica gel, using CH2 Cl2 (100): 2-propanol (10): NH * OH (0.5) used as the mobile phase Further purification is achieved by additional HPLC chromatography on Sil'tca, using CH2 Cla (100): CH3 OH (2.5): NH «OH {0.5) as the mobile Phase used The leveled fractions give the title compound (Relnheit-98%). Treatment of the product with an equivalent amount of 2N m HCl gives the hydrachloride salt of the title compound.

Analysis for Ci a Hs »Ns Sa * HCl: CHN 3 calculated 41.09 5.84 18.43 25.32% found: (corr. For 0.51% H2O) 40.78 5.63 18.31 s5.44% $ 0 Example 4: Preparation of N- [3 '(3-pyrrolidinomethytphBnoxy) propyl] -3thar] diimldamld-trihydrochloride A, N- [3- (3-pyrrolidinomethylphenoxyk) ropyl} -ethandiimldamide-ti1hydrochloride

A suspension of 13.4 g (38.3 mmol) of 3-amino-4- [3- (3-pyrrolidinome! Hyi-phenQxy) propylamino} -l, 2,5-fhiadiazole-1-oxide [prepared according to published QB patent application 2 067 987] in 350 ml of 55 methanol is treated with 25.5 ml of conc. HO, the resulting solution was stirred for 3 hours at room temperature, the solution was concentrated and then the water was removed azeotropically with absolute ethanol, the product being obtained. The crystalline residue was triturated with 150 ml of absolute ethanol, filtered and dried, giving 10.8 g of the Receives title link. Mp 195-203 ° C (dec.). 15

AT 397 655 B

Analysis for Ci s H25 NsO "3HCI: CHN calculated 46.55 6.84 16.92% found: 46.55 6.93 16.93% B. 3-Amino-4- [3- (3-i3yirolidinomethylphBnoxy) propy ] aminol-1,2,5-thiadiazoi

A stirred suspension of 8.25 g (20.0 mmol) of N-tfr (3-pyrrole-non-methylphenoxy) propyl] -äthandümidamid trthydrochloiid (prepared in step A) in 80 ml of DMF is treated with 5.4 g of {40.0 mmol ) Sulfur monochloride, stirring for 3 hours under a nitrogen atmosphere and concentrating the reaction mixture, whereby a dark gravel, rubber-like product is obtained which is suspended in 500 ml of water. If you make basic with K2CO3, extract with 3 x 100 m (methylene chloride, the extracts dry over MgSO 4 ", Filtered and concentrated to give 7.5 g of a dark gummy product. This is purified by apparatus HPLC chromatography on Siica using CH2 Cfe (100): 2-propano1 (5): NH" .OH {0 , 5) used as a mobile phase. The fractions containing the desired product are combined and concentrated to give 1.64 g (24.6%) of the purified title compound. Treatment of the product in absolute ethanol with an equivalent amount of 2N HCl gives the hydrochloride salt of the title compound (1.13 g ), Mp. 138-140 ° C.

Analysis for Ci «H» NbOS * HCI: C H N S calculated 51.95 6.54 18.93 8.67% found: 51.97 6.36 18.63 8.76%

Example 5 Preparation of N-methyl-N43- {5-piperidinomethylphenoxy) propyll-a ^ andiimidamide trihydrochloride

A suspension of 4.13 g (10.9 mmol) of 3-methyamino-4-i3- (S-piperidmomethylphenoxy) -propyiaminoJ-1,2,5-thiadiazoM-owd (prepared in accordance with published GB patent application 2,067 987] in 95 ml of methanol with 7.2 ml of concentrated HCl, stirred for 3 hours at room temperature, concentrated the solution and triturated the residue with acetone, then filtered and dried to give 4.35 g (90.4%) of the desired A sample of this is recrystallized from aqueous isopropyl alcohol to give the titled compound, mp 207-225 ° C. (dec.).

Analysis for CiaH2sNbO-3HCl: CHN calculated 49.03 753 15.89% found (corr. For 0.94% H20) 49.37 7.35 15.71% B. 3-methytamino-4- [3- (3-piperidinomethylphenoxy) -propylaminoH, 2.5- thiadiazole A mixture of 3.74 g (8.47 mmol) of N-M9thyl-N, - [3- (3-piperidinomethylphenoxy) propyi &gt; Mthandiimida-mid-trihydrochloride [prepared in Step A], 34 ml of CH2Cl2 and 3.5 ml of triethylamine treated with 3.36 g (8.46 mmol) of N.N'-thiobisphthalimide (DMF solvate) and stirred for 1 hour. The mixture is then washed with 30 ml of 10% KOH, dried (MgSQt) diluted with toluene and concentrated to give 3.6 g of the product. This product is purified by &quot; Rash &quot; chromatography on 90 g of silica gel (63-38 µm, (230 to 400 mesh)) using ethyl acetate-methanol (95: 5) as a detergent. 1.8 g (62%) of the title compound are obtained. Treatment of this product with an equivalent amount of aqueous HCl in 1-propanol gives the hydrochloride salt of the component, mp 163.5 to 164.5 ° C. 16

AT 397 655 B

Analysis for Cist ^ NsOS-HCI: C H N S CI calculated 54.32 7.04 17.60 8.06 8.91% found: 54.% 7.07 17.64 8.36 8 £ 6%

Example 6: Preparation of fFBenzyl-NM> (3-piperidinoroethylphenoxy) propy1] gteandiimidarnid-trihyctro-io chloride A. N-benzyl-N * - [3- &lt; 3-pipgridinomethylphenoxy) propvi] äthandlimldamld-trihydrochtorid. A suspension is added 5.14 g (11.3 mmol) of 3-benzytamino-4 ~ [3- {3-pIperldirramethylphenoxy) -propy {aminoh1.2, S-! HiaicBa2ol-1-oxide [made according to published GB patent application 2,067 is 9871 in 100 ml of methanol with 7.5 ml of conc. HCl, stirred for 3 hours at room temperature, concentrated the solution and triturated the residue with acetone. Then it is filtered and dried, giving 5.16 g (88%) of the compound, mp. 187-205 ° C. (dec.)

Analysis for C2 * Hg3NsO-3HCI: CHN Ci calculated 55.75 7.03 13.55 20.57% found: 54.88 6.75 13.33 20.20% 25 B. 3-benzylamino-4- [3 »(3-pip6iidinomethylphenoxy) propylamlnol-l, 2,5-thiadiazole A mixture of 4.73 g (9.16 mmol) of N-benzyl-N '- [3- (3-piperidinomethylphenoxy) propylh äthandiimidamide-tihydrochloride [ prepared in step A], 45 ml of CH2Q2 and 3.8 ml of triethylamine with 3.64 g ¢ 9.16 mmol) of N.N'-thiobisphthalimide (DMF solvate) and stirred for one hour. The mixture is then washed with 44 ml of 10% KOH, dried (MgSOt), filtered, diluted with toluene and concentrated. The residue is chromatographed on 110 g of silica gel (63-38 μm, (230 - 400 mesh, using ethyl acetate as the eluent, 3.1 g (77%) of the title compound is obtained and treatment of this product with an equivalent amount of aqueous HCl in 2-propanot gives the hydrochloride salt of the title compound, mp 138-141 ° C 35

Analysis Cz + Hsi Ns OS · HCl; C H N S CI calculated 60.80 6.80 14.77 6.76 7.48% found: 60.53 6.64 14.99 6.91 7.47%

Example 7; Preparation of N- {2 - [(5-DimBthylaminomethyl-3-ihienyl) methylteio] ethyrFäthandiinndamid-trih-46 ydrochlprid A. N-f2 - [(5-Oimethylaminomethyl-3-thienyl) methylthioIäthyl &gt; -äthandrimidamid4rihydiOChlorid 8 g (22.6 mmol) of 3-amino-4- {2 - [{5-dimethyaminomethyl-3-thieny {) methylth! 0} -ethy) amino) * l, 2,5-thladiazoM-oxide [prepared according to the published GB patent application 2 o67 so 987] in 150 ml of methanol, 115.0 ml of conc. HCl, stir for 3 hours at room temperature and then concentrate the solution. The residue is triturated with 1-propanol, filtered and dried, giving 7.36 g (80%) of the product. A sample is recrystallized from methanol-acetone to give the title compound, mp. 190-205 ° C, (dec.}. 17 55

AT 397 655 B

Analysis Ci2N2jN582 * 3HCI: CHN calculated: found: 3525 35.03 5.92 5.93 17.13% 17.39% B. 3-Amino-4 “{2 - [(5'dimethyiaminomathyl-3-thienyl) rnethylthio] ethylarnino'H , 2,5-thiadiazole A mixture of 6.13 g (15.0 mmol) of N- {2 - [(5-Dimefeylamlnomethyl-3-thieny!) Methylthio} · io ethyl} äthandiimidamid-trihydrochiorid [prepared in step A] , 60 mt CH2CO2 and 6.3 ml TriSthyiamin are treated with 5.96 g (15.0 mmol) Ν, Ν'-thiobisphthalimide {DMF solvate), stirred for 1 hour, the mixture is washed with 100 ml 10% KOH , dries (MgSO *), filtered, diluted with toluene and concentrated to give 5.1 g of the product. Treat the product with 0.5 molar equivalents of fumaric acid in 1-propanoi to give the fumaric acid acid of the compound, mp 141-143 ° C. The NMR-15 spectrum in DMSO-de shows the presence of approximately 0.12 moles of 1-propanol.

Analysis for (Ci2Hi9hfeS3) 2 * G <.H4O4. »0.12 CaH8O: CHNS calculated 43.68 5.61 17.75 24.38% found: 43.41 5.53 17.54 24.24% 25 Bel &amp; plei 8: Production of N-l2 - [(5-piperidlnomefhyl-3-frienyl) methylthio] ethylväthan &quot; diimto-trihydrochio-rid A. N- {2 - [(5-piperidinomethyl-3-thienyl) mathyithto] -gthyl &gt; äthan-diimidamid-tTihydrochtorid A suspension of 6.1 g (15.8 mmol) 3-Amino-4- {2 - [(5-piperidinometoyl-3-fttenyl) m6thyith! Ol · 30 äthyismino} -1 ^, 5 -th (adiazol-i-oxide [prepared according to published GB patent application 2,067,967] in 80 ml of methanol is treated with 10.5 ml of concentrated HCl, stirred for 3 hours at room temperature and then the solution is concentrated. The residue is triturated with 50 ml of 1-propanol, filtered and dried to give 5.66 g (83%) of the product. A sample is recrystallized from metfianof / acetone to give the title compound, mp 201-214 “C (dec. ). ss

Analysis Ci s HkNbS2 »3HCI: C H N S calculated: found: 40.13 30.07 6.29 8.47 15.60 15.28 14.29% 14.63%. . B.3-Amino-4- {2-i (5-piperidinomethyl-34hienylmethylthio3-ethylamine,) - i, 2,5-thiadiazole

A mixture of 5.17 g (11.5 mmol) of N- {2 - [(5-Pipsrtdinomethyl-3-thienyi) -methymwl · «5 äthyl} äth8ndimidamid-Whydrochlorid [prepared in Mare A], 48 ml of CH2Cl2 and 4 , 8 ml of triethylamine are mixed with 4.57 g (11.5 mmol) of N.N'-thiobispftthaiirnid (DMF solvate). stirring for 1 hour, the mixture washes with 90 mlg 10% KOH. dries (MgSOt), filtered, diluted with toluene and concentrated to give 4.5 g of the product. Treatment of the product with 1 equivalent of cyclohexylsuifa-mldic acid in methanol gives the cyclohexylsulfamate salt of the compound, mp 142-143 ° C. 60

Analysis for CisHggNsSa ^ CeHiaNOaS: C H N S calculated: found: 45.96 45.61 6.61 6.41 15.31 15.46 23.38% 23.48 18

Claims (9)

AT 397 655 B Claims 1. Process for the preparation of a compound of the general formula in which R1 is a hydrogen atom, (lower} Aikyi. Or 15 20 means 25 where p is 1 or 2 and Rz and R3 each independently represent a hydrogen atom, (low) aikyi, (low) alkoxy or haiogen atom, m is an integer from 0 to 2 inclusive, n is an integer of 2 until inclusive is 5: Z represents an oxygen * or sulfur atom or methylene, and AIQr where 50 FF is a hydrogen atom or (lower alkyl is q represents an integer from 1 to 4 inclusive and FF and R7 are each independently (ntedrtg) alkyl, or FF and R7, together with the nitrogen atom to which they are attached are a pyrroidino or piperidino radical, or a set, hydrates or Schrates thereof, characterized in that preferably in an inert solvent and at room temperature, a compound of the general formula 1Θ * - «aV» xCCiy n1® III 55 AT397 655B in which R1, A and Z and m and n have the meanings given above, with a strong inorganic acid, preferably hydrochloric acid. 2, Method according to claim 1, characterized in that as starting compounds of the general form! ill used those in which R1 is a hydrogen atom or <lower) alkyl, m for 0 or 1, π for 2 or 3. Z for an oxygen or sulfur atom and A for the formulas in which R5 represents a hydrogen atom or methyl, and R6 and R7 each independently represent methyl or ethyl, or, together with the nitrogen atom to which they are attached, form a pyrrolldino or piperidino ring. 3. The method according to claim 1, characterized in that one is used as the starting compound of the formula III in which the radical A- (CH2) mZ <CHa) n- for the group so 3S is where R6 and R7 are each methyl or, together with the nitrogen atom to which they are attached, is a pyrroidino or piperidino ring, and R1 in the starting compound III is a hydrogen atom or methyl. 40 4. The method according to claim 1, characterized in that one is used as the starting compound of the formula Iti, in which the radical A - (CHs) m Z (CHa) a- 4 $ for the group so SG is where R5 is independently hydrogen or methyl, R6 and R7 are independently methyl or ethyl and R1 in the starting compound lii is a hydrogen atom 20 AT397 666B or methyl &amp; The method of claim 1 thereby gnhermTolctmot. that from the initial connection Ui honor such is used in the rest A - (CHzU Z (Ofe), - for cfle group see, where ff is independently of R1 a hydrogen atom or methyl and ff and ff each independently represent a methyl · or ethyl radical, and A1 in the starting compound Ui is a hydrogen sulfate or methyl 6. The method according to claim 1, thereby flakentvcafchngt. from the starting compound of the formula 013-amino-4- {3- (3-plperidinone &gt; elhylphenoxy) propytan) ino} -1 .itS-thiaciazoH -oadd 7. The method according to claim 1, thereby tonrrroichnat, that from the starting compound of the formula Hl 3-AmkK) ^ - ^ (5-cimeteylarnteoniethyK2-furyl) metryBhioPihylarnino) -1,2,5-WadlazoM-oxkl &amp; A method according to claim 1, characterized in that starting from the starting compound the name 01 3-aminc> -4- {2 ^ (^ im8thylarninomethyi-i-meihyF2-thienyi) m8fiiy0hfo] gflrytamino} -1 AS-fhtatBazoM-oxide is used 9. The method according to claim 1, characterized in that from Auegangareprtndungung of formula IB 3-Amirx &gt; -4-i3-0-i ^ rrolkenom0tt »y» -phenmiy) propyiamino &gt; 1 ^^ thisdtezol-l-OKid is used 10. The method according to claim 1, characterized gnjnennrelntwmt. from the initial connection JMmino - '*' {2 ^ &lt; tFt0methylanilnome &amp; iyF3-tfttenyf) ine &gt; hylthlogthyfamino} -1. 2,54hiacBazoi-1-axkl used 11. The method according to claim 1, characterized in that starting from the starting compound of the formula 10 3-Amteo ^ 2 ^ piSperidir »inethyl-31trtenyl) meihylthte} -aihytemino) -12, SHhiacSazol-l-oxide 21 is used